Quaternary ammonium salts of indole derived acids



United States Patent 3,270,023 QUATERNARY AMMONIUM SALTS 0F INDOLEDERIVED ACIDS Edward Griflin Shay, Belle Mead, N.J., and Reginald L.

Wakeman, Philadelphia, Pa., assignors to Millmaster Onyx Corporation,New York, N.Y., a corporation of New York No Drawing. Filed Aug. 12,1965, Ser. No. 479,274

18 Claims. (Cl. 260-286) This invention has for its object thepreparation of relatively water-insoluble, microbiologically activequaternary ammonium compounds obtained by the reaction of water-soluble,bacteriologically active quaternary ammonium compounds withwater-soluble salts of aromatic acids derived from indole.

This application is a continuation-in-part of Serial No. 359,500, filedApril 13, 1964.

The indole-derived acids which may be used in this invention correspondto the following formula:

in which X may be 0 o 0 I lOH, l( lOH 0r (IJOH (wherein the double bondis linked to a carbon of Y); Y may be or H; and Z may be H, Cl, Br, F,N0 OH or low molecular weight alkyl or aryl. Examples of suitable acidsinclude isatin or isatic acid, isatoic acid, indoxylic acid, 7-chloroisatic acid, -chloro isatoic acid, isatin-3- (pnitrophenyl hydrazine),S-nitro isatic acid, S-nitro isatoic acid and the like.

The compounds of this invention can be prepared by mixing an aqueoussolution of a water-soluble salt of the aromatic acid with an aqueoussolution of a quaternary ammonium salt having microbiologically activeproperties. The two solutions are thoroughly mixed and are then allowedto stand until they separate into two distinct layers. The upper layerwill normally contain the compound of the present invention. Layerseparation is conveniently effected by conducting the reaction in aseparatory funnel and drawing oh the desired layer. The product usuallycontains some water which can be removed by distillation or drying in avacuum oven. The aqueous product layer can, however, be used in anyprocess where the entrapped water would not be harmful.

Typical examples of the quaternary ammonium compounds which may be usedin this invention are the alkyl trimethyl ammonium chlorides,alkyl-benzyl trimethyl ammonium chlorides, alkyl dirnethylbenzylammonium chlorides, alkyl dimethyl menaphthyl ammonium chlorides, alkyldimethyl substituted-benzyl ammonium chlorides in which the benzylradical is substituted with one or more side chains containing from 1 to5 carbon atoms such, for example, as methyl, dimethyl, ethyl and thelike and in which the carbon atoms may all be in the same or differentside chains or in which the benzyl radical bears one, two or morehalogen atoms such as chlorine or bromine, alkyl pyridinum chlorides,alkyl isoquinolinium chlorides and bromides, alkyl lower-alkylpyrrolidinium chlorides, alkyl lower-alkyl morpholinium chlorides in allof which the alkyl group may have from 8 to 22 carbon atoms and thelower alkyl group may have from 1 to 5 carbon atoms and alkyl phenoxyethoxy ethyl dimethylbenzyl ammonium chloride in which the alkyl radicalmay be iso-octyl or nonyl and in which the benzyl radical may, ifdesired, be substituted by a methyl radical. Various other analogs ofthese quaternaries may also be employed such, for example, as cetyldimethyl ethyl ammonium bromide or oleyl dimethyl ethyl ammoniumbromide.

In general, the quaternary ammonium compounds useful in this inventionare the higher alkyl quaternary ammonium hydroxides, halides (chloridesand bromides), sulfates, methosulfates and the like possessing thefollowing formula:

where R is an alkyl or alkaralkyl radical containing from 8 to 22 carbonatoms or an alkyl phenoxy ethoxy ethyl radical in which R is an alkylradical containing from 8 to 9 carbon atoms and in which the phenylradical may be substituted by a methyl group; R and R" are methyl orethyl radicals or members of a heterocyclic ring system such aspyridine, isoquinoline, pyrrolidine and morpholine; R is a methylradical or a benzyl group or a substituted-benzyl group such, forexample, as a monochlorobenzyl radical or a dichlorobenzyl radical ormixture thereof or a methyl benzyl, dimethyl benzyl, ethyl benzyl,diethyl benzyl, isopropyl benzyl, tertiary butyl benzyl, isoamyl benzylor another benzyl radical containing from 1 to 5 carbon atoms as sidechains, either as a single side chain or a multiplicity of side chainsincluding mixtures thereof or a menaphthyl group or hydrogenatedmenaphthyl group. When R or R" are members of a morpholine orpyrrolidine ring, R' is a methyl, ethyl, propyl or butyl group. When Rand R" are members of an unsaturated heterocyclic ring such as pyridineor isoquinoline, R is the same radical as R". X in the above formulacorresponds to a halide radical such as chloride, bromide or iodide, orto any other water-soluble anion such as methosulfate.

After thorough mixing in the manner previously described, the organicproduct layer is separated from the aqueous layer (as with a separatoryfunnel) since two distinct phases are formed. Separation may befacilitated by the addition of an organic solvent immiscible with water.The product layer may be washed with water to remove any residualby-product salt or unreacted materials. The solvent, if any, may beevaporated and the product air or vacuum dried to a paste, wax, oil orsolid.

It is not necessary to use an aqueous medium. Any solvent or solventmixture in which the starting materials are soluble will besatisfactory. Non-aqueous solvents facilitate the separation ofby-product inorganic salt and reduce the need for vacuum drying to getan anhydrous product. When a non-aqueous medium is employed, it isusually necessary to add a small amount of water to facilitate ionicreaction.

An alternative method for the preparation of compounds especiallyapplicable to the treatment of fabric, ropes, net, woven and non-wovenfabric and reticulated or convoluted materials involves a two-stepprocess. In the first step, the material is passed through a bathcontaining the anionic moiety. Excess solution is removed by methodswell known to those skilled in the art. The treated material is thenpassed through a second bath wherein the concentration of quaternaryammonium compound is such that the material pickup will result in anequivalent amount of quaternary ammonium compound reacting with theanionic moiety, depositing the product be formulated as waterdispersions by dissolving them in a Walter-miscible organic solvent suchas acetone or methanol and diluting with water or by dissolving them inemulsifiable oils such as, for example, sulfonated castor oil or pineoil and diluting with water. In preparing aqueous dispersions,emulsifying agents such, for example, as ethylene oxide condensates ofalkyl phenols may be used with or without organic solvents.

It is surprising that the compounds of this invention exhibit highmicrobiological activity despite their relative insolubility in water.Because of their unusual combination of physical and microbiologicalproperties, they can be used to impart laundry-resistant anti-microbialcharacteristics to textiles. They can also be used as the active agentin anti-mildew finishes for textiles which are resistant to leachingwith water.

Although the compounds have low water solubility, they are compatiblewith various organic solvents, plasticizers and high molecular weightcompounds. Consequently, they may be incorporated as anti-microbialagents in synthetic resins and plastics. The compounds are compatiblewith natural and synthetic rubber latices. Therefore, they may be usedto prepare bacteriostatic films and molded objects deposited from suchlatices.

The compounds can be incorporated into cutting and grinding fluidswithout precipitation. Also, they blend well with non-ionic and anionicsurface-active agents. In such compositions they retain theirmicrobiological activity.

It will be understood that the properties of the products describedherein will vary depending upon the nature of the cationic quaternaryammonium compound used in their preparation as well as the anioniccompound reacted therewith.

The chemical, physical and biological properties of the products of ourinvention make them especially appropriate for the followingapplications when suitably incorporated in active amounts in anappropriate vehicle, binder, medium or substrate:

(1) Mildewproofing fabric, canvas, ropes, textiles, awnings, sails,tenting and other woven and non-woven reticulated materials.

(2) Paint mildewstats.

(3) Jet plane fuel additive to control growth of microor' ganisms.

(4) Odor preservative agents for clothes and shoes.

(5) Mildew retardant and odor suppressant for shoes and other leatherproducts.

(6) Topical antiseptics.

(7) Antidandrutf agents.

(8) Disinfection agents for hair and gut of man and beast.

(9) Bacteriostatic furniture dressing.

(10) Surface finishes for stone, plaster, tile, cement, brick and otherinorganic building materials to retard growth of microorganisms, fungi,mold and algae.

(11) Wool perservative.

( 12) Plant and tree spray to combat fungi.

(13) Antimycotic agents for soap wrappers.

(l4) Self-sanitizing brushes.

(15) Mildewproofing agent in and on plastic and film.

(16) Mildewproofing of cellulosics, cardboard, fibreboard,

paper and cordage.

(17) Contact biostat for application to film, waxes and cloth topreserve cheese, meats and vegetables and other food products.

(18) Algal inhibition, especially on surfaces and in solution where lowfoaming is desirable.

(19) Paper pulp slime control.

( 20) Sanitizing agent for rug, carpet, curtains.

(21) Egg preservation.

(22) Adhesive preservation.

(23) Preservation of latex paints.

(24) Preservation of metal-working compounds.

(25) Additives for soap and for both anionic and nonionic deter-gents inliquid, bar,.powder, bead, solution and other forms to impartbacteriostatic and fungistatic properties thereto.

(26) Ba'cteriostats, fungistats and algistats for the treatment ofindustrial cooling waters as in cooling towers, air conditioners andhumidifiers and for use in secondary oil recovery.

The microbiological activity of our compounds has been evaluated formicrobiological stasis by the Standard Tube Dilution Test, the techniquefor which is common knowledge to those skilled in the art. A Difco BactoCSMA Broth #0826 was used in the study. This test is used to determinethe lowest concentration of microibiologically active compounds whichwill inhibit the growth of the organism in question. For a wide range ofapplications, the inhibition of growth rather than outright kill issatisfactory.

Briefly put, the Tube Dilution Test consists in placing 9 cc. of theCSMA Broth in a test tube which is then sterilized in an autoclave. Onecc. solution of the microbiologically active compound at an appropriateconcentration is added to the test tube which is then inoculated with0.1 cc. of a twenty-four hour old culture of the organism under study.The test tube is then incubated at 37 C. for fortyeight hours andobserved for bacterial growth.

The same procedure is followed for fungi. In such tests, however, thetubes are incubated for fourteen days at a temperature suitable foroptimum fungal growth, usually 25 C.

The invention is illustrated by, but not restricted to, the followingexamples:

Example I A 10% aqueous solution of the sodium salt of isatin (2,3indolinedione) was prepared. 222 grams of this solution was charged intoa separatory funnel and to it was added 410 grams of a 10% solution ofalkyl dimethyl ethyl-benzyl ammonium chloride =(BTC471Onyx ChemicalCompany, alkyl distribution being 50% C 30% C 17% C 3% C and a littlebenzene to facilitate phase separation, and the funnel was well shaken.The product layer was separated and dried in a vacuum oven to yieldalkyl dimethyl ethyl-benzyl ammonium isatate in 98% of the theoreticalyield as a red paste.

Example II Using equimolar quantities of the solution of sodium isatateof Example I and of a solution of alkyl dimethyl benzyl ammoniumchloride (BTC824-Onyx Chemical Company, alkyl distribution being 60% C30% C 5% C 5% C and following the same procedure, 98% of the calculatedyield of alkyl dimethyl benzyl ammonium isatate was recovered as anorange paste.

Example III Using equimolar quantities of the solution of the sodiumsalt of isatin of Example I and of a 10% aqueousalcoholic solution oflauryl isoquinoliniurn bromide (Isothan QOnyx Chemical Company), andfollowing the procedure described in Example I, a dark red paste wasobtained in 100% yield of lauryl isoquinolinium isatate.

Example IV A 0.1 molar solution of the mono-potassium salt of isatoicanhydride was prepared in water. An aliquot of this solution was treatedas in Example I with an equimolar amount of a solution of the alkyldimethyl ethylbenzyl ammonium chloride of Example I. Alkyl dimethylethyl-benzyl ammonium isatoate was recovered in substantially thetheoretical yield as a brown paste.

Example V An aliquot of the mono-potassium isatoate of Example IV wastreated in the same manner with an equimolar amount of the laurylisoquinolinium bromide of Example III. The product, laurylisoquinolinium isatoate was recovered as a dark red paste in thetheoretical yield.

Example VI A 0.254 normal solution of alkyl dimethyl benzyl ammoniumchloride of Example H was reacted in stoichiometric proportions with themono-potassium isatoate of Example IV and in the same manner. Alkyldimethyl benzyl ammonium isatoate was obtained in substantially thetheoretical yield as a brown paste.

Example VII Using the Standard Tube Dilution Test described above, thefollowing bacteriostatic levels were determined (S.a.=Staphylcoccusaureus; S.t.=Salmonella typhosa; A.n=Aspergillus niger):

Baeteriostatic Dilution Level vs.- Product from Example No.

8.11. Si. A.n

Example VIII Example IX In the same manner as in Example V, mono(1aurylisoquinolinium) S-chloroisato'ate and mono(lauryl isoquinolinium)S-nitroisatoate were prepared from the respective 5-chloroisatoic landS-nitroisatoic acids. Similarly, the alkyl dimethyl ethyl-benzylammonium and alkyl dimethyl benzyl ammonium salts of 5-chloroisatoicacid and 5-nitroisatoic acid may be prepared by the respectiveprocedures of Examples IV and VI.

We claim:

1. The quaternary ammonium salt of an indole derived acid selected fromthe group of isatic acid, isatoic acid, the 5- and 7-chloro isatic andisatoic acids and the S-nitroisatic and isatoic acids, the quaternarycation thereof being derived from a quaternary ammonium compound havinga phenol coefiicient of at least with respect to both Staphylococcusaureus and Salmonella typhosa at 20 C. and having an alkyl of from 8 to22 carbon atoms.

2. Alkyl dimethyl ethyl-benzyl ammonium isatate, the alkyl having 12 to18 carbon atoms.

3. Alkyl dimethyl benzyl ammonium isatate, the alkyl having 12 to 18carbon atoms.

4. Lauryl isoquinolinium isatate.

5. Alkyl dimethyl ethyl-benzyl ammonium 7-chloroisatate.

6. Alkyl dimethyl ethyl-benzyl ammonium S-nitroisatate.

7. Alkyl dimethyl ethyl-benzyl ammonium 7-chloroisatate.

8. Alkyl dimethyl benzyl ammonium 7-chloroisatate.

9. Lauryl isoquinolinium S-chloroisatate.

10. Lauryl isoquinolinium 7-chloroisatate.

11. Lauryl isoquinolinium S-nitroisatate.

12. Mono(lauryl isoquinolinium) S-chloroisatate.

13. Mono(laury1isoquinolinium) S-nitroisatate.

14. Alkyl dimethyl ethyl-benzyl ammonium S-chloroisatate.

15. Alkyl dimethyl benzyl ammonium S-chloroisatate.

16. Lauryl isoquinolinium isatoate.

17. Alkyl dimethyl ethyl-benzyl ammonium isatoate.

18. Alkyl dimethyl benzyl ammonium isatoate.

OTHER REFERENCES Elderfield, Heterocyclic Chemistry, vol. III, Wiley,1952, pp. 63 and 215.

Hope et al., abstracted in Chem. Abstr., vol. 7, col. 2217-8.

Schwartz et al., Surface Active Agents and Detergents, vol. II,Intersciences, 1958, pp. 211 and 222.

ALEX MAZEL, Primary Examiner. HENRY R. JILES, Examiner.

DONALD G. DAUS, Assistant Examiner.

1. THE QUATERNARY AMMONIUM SALT OF AN INDOLE DERIVED ACID SELECTED FROMTHE GROUP OF ISATIC ACID, ISATOIC ACID, THE 5- AND 7-CHLORO ISATIC ANDISATOIC ACIDS AND THE 5-NITROISATIC AND ISATOIC ACIDS, THE QUATERNARYCATION THEREOF BEING DERIVED FROM A QUATERNARY AMMONIUM COMPOUND HAVINGA PHENOL COEFFICIENT OF AT LEAST 100 WITH RESPECT TO BOTH STAPHYLOCOCCUSAUREUS AND SALMONELLA TYPHOSA AT 20*C. AND HAVING AN ALKYL OF FROM 8 TO22 CARBON ATOMS.
 9. LAURYL ISOQUINOLINIUM 5-CHLOROISATATE.